Acute Gain in Minimal Lumen Area Following Implantation of Everolimus-Eluting ABSORB
Biodegradable Vascular Scaffolds or Xience Metallic Stents
Intravascular Ultrasound Assessment From the ABSORB II Trial
Yohei Sotomi, MD,aYuki Ishibashi, MD, PHD,bPannipa Suwannasom, MD,a,b,cShimpei Nakatani, MD,b Yun-Kyeong Cho, MD, PHD,bMaik J. Grundeken, MD,aYaping Zeng, MD, PHD,bHiroki Tateishi, MD, PHD,b Pieter C. Smits, MD, PHD,dPaul Barragan, MD, PHD,eRan Kornowski, MD,fAnthony H. Gershlick, MD, PHD,g Stephan Windecker, MD, PHD,hRobert-Jan van Geuns, MD, PHD,bAntonio L. Bartorelli, MD, PHD,i
Robbert J. de Winter, MD, PHD,aJan Tijssen, MD, PHD,aPatrick W. Serruys, MD, PHD,jYoshinobu Onuma, MD, PHDb
ABSTRACT
OBJECTIVESThe study compared, by intravascular ultrasound (IVUS), acute gain (AG) at the site of the pre-procedural minimal lumen area (MLA) achieved by either the Absorb (Abbott Vascular, Santa Clara, California) scaffold or the Xience stent and identified the factors contributing to the acute performance of these devices.
BACKGROUNDIt is warranted that the acute performance of Absorb matches that of metallic stents; however, concern exists about acute expansion and lumen gain with the use of Absorb.
METHODSOf a total of 501 patients (546 lesions) in the ABSORB II (ABSORB II Randomized Controlled Trial) ran- domized trial, 445 patients with 480 lesions were investigated by IVUS pre- and post-procedure. Comparison of MLA pre- and post-procedure was performed at the MLA site by matching pre- and post-procedural IVUS pullbacks.
RESULTSLower AG on IVUS (lowest tertile) occurred more frequently in the Absorb arm than in the Xience arm (3.46 mm2vs. 4.27 mm2, respectively; p< 0.001; risk ratio: 3.04; 95% confidence interval: 1.94 to 4.76). The plaque morphology at the MLA cross-section was not independently associated with IVUS acute gain. The main difference in AG in MLD by angiography was observed at the time of device implantation (Xience vs. Absorb,Dþ1.50 mm vs.Dþ1.23 mm, respectively), whereas the gain from post-dilation was similar between the 2 arms (Dþ0.16 mm vs.Dþ0.16 mm) when patients underwent post-dilation, although expected balloon diameter was smaller in the Absorb arm than in the Xience arm (p¼ 0.003) during post-dilation.
CONCLUSIONSAt the site of the pre-procedural MLA, the increase of the lumen post-procedure was smaller in the Absorb-arm than in the Xience arm. To achieve equivalent AG to Xience, the implantation of Absorb may require more aggressive strategies at implantation, pre- and post-dilation than the technique used in the ABSORB II trial.
(ABSORB II Randomized Controlled Trial [ABSORB II];NCT01425281) (J Am Coll Cardiol Intv 2016;9:1216–27)
© 2016 by the American College of Cardiology Foundation.
From theaHeart Center, Academic Medical Center, Amsterdam, the Netherlands;bThorax Center, Erasmus Medical Center, Rotterdam, the Netherlands;cNorthern Region Heart Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;
dMaasstad Ziekenhuis, Rotterdam, the Netherlands;ePolyclinique les Fleurs, Ollioules, France;fRabin Medical Center, Petah Tikva, Israel;gGlenfield Hospital, Leicester, United Kingdom;hBern University Hospital, Bern, Switzerland;iCentro Cardiologico Monzino, University of Milan, Milan, Italy; and thejInternational Centre for Circulatory Health, NHLI, Imperial College London, London, United Kingdom. The ABSORB II study was sponsored by Abbott Vascular. Dr. Sotomi is a consultant for Goodman; and has received grants from Fukuda Memorial Foundation. Drs. Onuma and Serruys are on the advisory board of Abbott Vascular. Dr. Smits has received research grants, speaker fees, and honoraria from Abbott Vascular, St. Jude Medical, and Terumo. Dr. Windecker has
The fully bioresorbable scaffold is a novel device to treat coronary artery stenosis, potentially minimizing the long-term compli- cations seen with metallic drug-eluting stents. The everolimus-eluting Absorb bioresorbable vascular scaffold (Absorb, Abbott Vascular, Santa Clara, California) made of poly-L-lactide (PLLA) provides a temporary coronary scaffolding for at least 6 months and becomes fully resorbed by approximately 3 years (1). Thefirst-in-humans trial using the Absorb showed excellent safety results with potential late benefits such as late lumen enlargement and restoration of vas- omotion(2). The ABSORB II (ABSORB II Randomized Controlled Trial;NCT01425281) study is thefirst ran- domized trial between the Absorb scaffold and Xience metallic stents in patients with up to 2 de novo native coronary lesions(3,4).
It is warranted that the acute performance of Absorb matches that of metallic stents; however, concern exists about acute expansion and lumen gain with the use of a polymeric device. In the ABSORB first-in-humans trial, post-procedural intravascular ultrasound (IVUS) imaging demonstrated that im- plantation of an Absorb scaffold resulted in a more eccentric lumen with nonhomogeneous scaffold expansion compared with metallic stents (5).
Furthermore, nonrandomized matched population from the ABSORB and SPIRIT trials demonstrated that angiographic acute gain in lumen diameter tends to be smaller in the Absorb than in the Xience (6).
This trend was also observed in the randomized Japanese ABSORB trial (7–9). In the ABSORB II randomized trial, pre-procedural and post-procedural documentary IVUS imaging were mandatory and provided a unique opportunity to evaluate the scaffold/stent expansion at the precise site of pre- procedural minimal lumen area (MLA) and to relate the degree of expansion to the mechanical perfor- mance of both devices, procedural parameters of implantation and tissue composition derived from IVUS analyses(4).
Therefore, the purpose of this study was to inves- tigate the IVUS acute gain at the site of minimal
lumen area between the Absorb scaffold and the Xience stent and to identify the factors contributing to the acute performance of these devices.
METHODS
STUDY DESIGN AND POPULATION. The ABSORB II study was a randomized controlled trial comparing the safety and efficacy of the Absorb everolimus-eluting bioresorbable vascular scaffold and the Xience everolimus-eluting metallic stent in patients with up to 2 de novo native coronary lesions. Details of the study are available elsewhere (3). After successful pre-dilation of the target lesion, 2:1 randomization was performed. Of a total of 501 patients (546 lesions), 335 patients (364 lesions) were randomly assigned to receive Absorb device, and 166 patients (182 lesions) were assigned to receive the Xience device. Grayscale IVUS and IVUS-virtual his- tology (VH) imaging pre-procedure and post- implantation was mandatory but documentary. No treatment recommendation on the basis of IVUS im- aging was made in the protocol.
STUDY DEVICE. The Absorb device has an amorphous poly-DL-lactide (PDLLA) coating that contains and controls the release of the antiproliferative drug ever- olimus. The scaffold is made of semicrystalline PLLA.
PLLA is completely biodegraded by hydrolysis into water and CO2 via the Krebs cycle. Physically, the scaffold has struts with an approximate thickness of 150mm. The Xience device is an everolimus-eluting, cobalt chromium alloy device with a platform consist- ing of serpentine rings connected by links fabricated from a single piece. The overall strut thickness including the drug coating is approximately 90mm.
PROCEDURE AND IVUS ACQUISITION.Pre-procedural IVUS was mandatory before dilation of the target lesion. If it was not technically feasible (e.g., the IVUS catheter could not cross the lesion), pre-dilation with a small balloon was allowed to facilitate the IVUS catheter insertion.
IVUS images were obtained with a rotational 45-MHz IVUS catheter (Revolution, Volcano Corp.,
SEE PAGE 1228
A B B R E V I A T I O N S A N D A C R O N Y M S
IVUS= intravascular ultrasound
MLA= minimal lumen area MLD= minimal lumen diameter QCA= quantitative coronary angiography
received institutional research grants from Abbott Vascular, Biotronik, Boston Scientific, Medtronic, Edwards Lifesciences, and St.
Jude Medical. Dr. van Geuns has received speaker fees and institutional research grants from Abbott Vascular. Dr. Bartorelli has received speaker fees and travel support from Abbott Vascular. Dr. Gershlick has received lecture fees from Abbott Vascular and AstraZeneca. Drs. Grundeken and de Winter have received institutional grants from Abbott Vascular. All other authors have re- ported that they have no relationships relevant to the contents of this paper to disclose. Drs. Sotomi and Ishibashi contributed equally to this work.
Manuscript received December 31, 2015; revised manuscript received February 29, 2016, accepted March 21, 2016.
Rancho Cordova, California). After intracoronary in- jection of 200 mg of nitroglycerin, IVUS pullbacks were performed with the use of an automated motorized device at a pullback speed of 0.5 mm/s.
Lesions were treated with routine interventional techniques that included mandatory pre-dilation with a balloon shorter and 0.5 mm smaller in diam- eter than the study device. The size of stent/scaffold was determined by the target vessel diameter, which was measured by pre-procedural on-line quantitative coronary angiography (QCA) (3,10). All patients enrolled in the ABSORB II trial were treated as fol- lows: 1) a 3.5-mm device was used when both the proximal and distal maximal lumen diameters were within an upper limit of 3.8 mm and a lower limit of 3.0 mm; 2) a 3.0-mm device was used when both the proximal and the distal maximal lumen diameters were within an upper limit of 3.3 mm and a lower limit of 2.5 mm; 3) a 2.5-mm device was used when both the proximal and the distal maximal lumen di- ameters were within an upper limit of 3.0 mm and a lower limit of 2.25 mm; and 4) scaffold/stent overlap was allowed. Post-dilation with a balloon shorter than the implanted scaffold/stent was performed at the
discretion of the operators. Post-procedural IVUS images were obtained at the end of the procedure (post-device implantation or post-dilation). All pull- backs were analyzed offline by an independent core laboratory (Cardialysis BV, Rotterdam, the Netherlands) using commercially available software (QIvus version 2.2, Medis, Leiden, the Netherlands).
MEASUREMENT OF ACUTE GAIN ON IVUS. To assess the acute performance of the Absorb and Xience stent at the site of the worst stenosis pre-procedure, the difference of lumen area between pre- and post- procedural IVUS images at the site of the pre- procedural minimal lumen area (MLA) was measured as acute gain in MLA. Pre-procedural MLA was defined as the smallest lumen area within the target lesion.
After identifying the frame of the pre-procedural MLA site, matching of pre- and post-procedural IVUS im- ages was performed by identifying common land- marks, such as side branches, bifurcations, large calcifications, or echogenic metallic marker on the device. Matching was performed using a dedicated software (QCU-CMS software, Medis). The pre- procedural image of the MLA was matched and
FIGURE 1 Study Flow Chart
Of 501 patients with 546 lesions, enrolled in the ABSORB II trial, 445 patients with 480 lesions (291 patients with 313 lesions in Absorb and 154 patients with 167 lesions in Xience) had both pre-procedural and post-procedural IVUS analyses for acute lumen area gain at the original minimal lumen area site. pts¼ patients.
compared with the post-procedural lumen area at the same site. The lower acute gain was defined as the lowest tertile from the whole population.
ANALYSIS OF IVUS AND PROCEDURAL PARAMETERS.
Contour detection was performed by experienced IVUS core laboratory analysts who were unblinded to the device type. IVUS metrics including vessel, stent/
scaffold, and lumen area were measured at 0.5-mm intervals. To identify the lesion factors in the evalua- tion of acute gain, analysis was also performed using the following parameters: plaque burden, lumen ec- centricity, presence of calcium, remodeling index(11) from grayscale IVUS and tissue composition parame- ters (absolute value and percentage) from IVUS-VH.
Plaque burden was obtained by the plaque plus me- dium cross-sectional area divided by the vessel cross- sectional area(12). Eccentricity index was calculated as the ratio of the projected minimal and maximal lumen or scaffold/stent diameter at the MLA cross- section (5,13). Pre-treatment reference segments were selected as sites with the least amount of plaque proximal and distal to the MLA sites before the take- off of any major side branch(11). The remodeling in- dex (RI) was calculated as the vessel area at the MLA site divided by the average of the proximal and distal reference vessel areas. Negative remodeling was defined as an RI <0.88, intermediate remodeling as an RI of 0.88 to 1.00, and positive remodeling as an RI
>1.00(11).
Location and circumferential distribution of cal- cium was quantified in grayscale IVUS. Calcium was defined as bright echoes with acoustic shadowing.
The location of the calcium was defined as superficial, deep, or both(14). If the leading edge of the acoustic shadowing appeared within the shallowest 50% of the plaque thickness, it was defined as superficial cal- cium. If the leading edge of the acoustic shadowing appeared within the deepest 50% of the plaque thickness, it was defined as deep calcium. The largest continuous arc of calcium and summed arc of calcium at the site of pre-interventional lumen area were measured in degrees with a protractor centered on the lumen. In addition, the arc of calcium was classified as 1 quadrant (#90), 2 quadrants (91 to 180), 3 quadrants (181to 270), or 4 quadrants (271to 360).
By IVUS-VH analysis, tissue at the site of pre- procedural MLA was divided into 4 basic plaque tis- sue components: fibrous tissue, fibrofatty tissue, necrotic core, and dense calcium(15).
In the compliance charts (pressure-diameter re- lationships) for Absorb and Xience (Prime, Xpedition, and so forth) provided by the manufacturer, the inner
TABLE 1 Clinical Characteristics and Procedural Variables (N¼ 445)
Absorb (N¼ 291)
Xience
(N¼ 154) p Value Demographics
Males 217 (74.6) 123 (79.9) 0.241
Age (y) 61 10 61 10 0.786
Current smoking 77 (26.5) 33 (21.4) 0.251
Lipid disorder requiring medication 201 (69.1) 116 (75.3) 0.258 Hypertension requiring medication 188 (64.6) 104 (67.5) 0.802
Diabetes mellitus 64 (22.0) 38 (24.7) 0.554
Stable angina 187 (64.3) 100 (64.9) 0.917
Body mass index (kg/m2) 27.8 4.1 28.1 3.7 0.542
Obesity (BMI$30 kg/m2) 67 (23.1) 44 (28.6) 0.208
Lesions (N¼ 480) 313 lesions 167 lesions
Pre-procedural angiography
Lesion location 0.184
Left anterior descending artery 146 (46.7) 81 (48.5)
Left circumflex artery 88 (28.1) 35 (21.0)
Right coronary artery 79 (25.2) 51 (30.5)
Lesion classification† 0.456
A 4 (1.3) 1 (0.6)
B1 181 (58.0) 85 (51.5)
B2 125 (40.1) 78 (47.3)
C 2 (0.6) 1 (0.6)
Quantitative coronary angiography Interpolated percent diameter
stenosis (%)
58.3 11.1 59.1 11.4 0.448
Minimal lumen diameter (mm) 1.08 0.32 1.07 0.31 0.627 Reference vessel diameter (mm) 2.60 0.37 2.64 0.40 0.327 Maximal diameter at proximal reference
segment (mm)
2.84 0.45 2.87 0.46 0.476
Maximal diameter at distal reference segment (mm)
2.69 0.45 2.74 0.43 0.258
Procedural variables Pre-dilation
Pre-dilation before IVUS 115 (36.7) 59 (35.3) 0.842
Pre-dilation performed 313 (100.0) 165 (98.8) 0.121
Nominal diameter of pre-dilation balloon (mm)
2.60 0.36 2.64 0.35 0.236
Maximal pressure during pre-dilation (atm) 12.2 3.0 12.5 3.1 0.300 Device implantation
Nominal diameter of device 0.139
2.5 mm 52 (16.6) 17 (10.2)
2.75 mm 0 (0) 1 (0.6)
3.0 mm 190 (60.7) 107 (64.1)
3.5 mm 71 (22.7) 42 (25.1)
Maximal pressure during device implantation (atm)
13.1 2.7 13.8 2.5 0.008*
Expected inner device diameter (mm) 3.34 0.33 3.28 0.33 0.109 Post-dilation
Post-dilation performed 194 (62.0) 102 (61.1) 0.844
Nominal diameter of post-dilation balloon (mm)‡
3.16 0.34 3.28 0.37 0.01*
Maximal pressure during post-dilation (atm)§ 15.3 3.2 16.7 3.4 0.001*
Expected diameter of post-dilation balloon (mm)§ 3.27 0.35 3.40 0.39 0.003*
Maximal expected diameter of balloon (with or without post-dilation) (mm)
3.37 0.33 3.38 0.36 0.896
Values are n (%) or mean SD. *p < 0.05. †Data were available in 477 lesions. ‡Data were available in 292 lesions. §Data were available in 290 lesions.
diameters of the devices were described. Expected device diameter was obtained from the device compliance chart, using the nominal device diameter and the maximal pressure during implantation. Dur- ing post-dilation, the expected balloon diameter was obtained from the balloon compliance chart data provided by the various manufacturers of balloons, using the nominal diameter of the balloon and the maximal pressure during the procedure. In case the pressure during the procedure exceeded the highest pressure on the chart, the highest diameter on the chart was used for the calculation.
ANGIOGRAPHIC ASSESSMENT.Online QCA analyses were undertaken by the sites before Absorb implan- tation to define Dmax (10), and pre- and post- procedural offline QCA were performed by an independent core laboratory (Cardialysis BV) using the coronary angiography analysis system (Pie Medical Imaging, Maastricht, the Netherlands). The minimal lumen diameter (MLD) changes at different phases of the procedure were measured before procedure, after device implantation, and immediately after post- dilation. Additionally, minimal diameter of balloon was measured during scaffold/stent implantation at
FIGURE 2 Representative Case of IVUS Acute Gain
Examples of IVUS pullbacks before (A–E) and after procedure (F–I). Vessel and lumen contours were drawn (C) at the site of pre-procedural minimal lumen area (dotted line in longitudinal view [E, F]). Calcium, defined as bright echoes with acoustic shadowing, was measured in its circumferential extension (largest continuous arc of calcium [solid arc]: 101.3, summed arc of calcium [solid and dotted arcs]: 214.1[B]), and location (superficial calcium). Tissue component (D) was assessed by IVUS-VH. After matching pre- (E) and post-procedural IVUS pullbacks (F), vessel and lumen areas were obtained at the corresponding site (H). Lumen area in C was 1.77 mm2and 4.87 mm2in H. Therefore, acute lumen gain was 3.10 mm2(green line¼ vessel contour; red line ¼ lumen contour; blue asterisk ¼ side branch; blue dagger ¼ calcification).
LA¼ lumen area; MLA ¼ minimal lumen area; IVUS-VH ¼ intravascular ultrasound-virtual histology.
maximal inflation pressure and during post-dilation at maximal inflation pressure.
Acute recoil was defined as follows: When a stent/
scaffold delivery balloon was used for stent/scaffold expansion, acute absolute stent/scaffold recoil was defined as the difference between the mean diameter of the stent/scaffold delivery balloon at the highest pressure at implantation of the stent/scaffold (X) and the mean luminal diameter of the stented/scaffolded segment after implantation (Y). Acute absolute stent/
scaffold recoil was calculated as: [X– Y]. When a post- dilation balloon was used in the procedure, acute ab- solute recoil was defined as the difference between the mean diameter of the post-dilation balloon at the highest pressure in the post-dilated segment (X0) and the mean luminal diameter after post-dilation (Y0). The angiogram of X and Y was performed in the same
angiographic view so that the 2 images were perfectly matched.
STATISTICAL ANALYSIS. Categorical variables are presented as counts and percentages. Continuous variables are presented as mean SD. A p value of <0.05 was considered statistically significant.
Generalized estimating equations modeling was per- formed to take into an account the clustered nature of
>1 stents/scaffolds per patient, which might result in unknown correlations among measurements within these scaffold clusters. Paired analysis was performed in the patients with analyzable pre- and post- procedural IVUS images. Logistic regression analysis was performed to find the relationship of the following factors with IVUS lower acute gain in lumen area: sex, age, obesity (body mass index$30 kg/m2),
TABLE 2 IVUS Data at the Site of Pre-Procedural Minimal Lumen Area (N¼ 480)
Data
Pre-Procedure Post-Procedure Change From Pre to Post
Absorb (n¼ 313)
Xience
(n¼ 167) p Value
Absorb (n¼ 313)
Xience
(n¼ 167) p Value
Absorb (n¼ 313)
Xience
(n¼ 167) p Value Grayscale IVUS
Lumen area (mm2) 2.08 0.76 2.13 0.85 0.502 5.55 1.46 6.40 1.68 <0.001 3.46 1.35 4.27 1.46 <0.001 Vessel area (mm2) 10.71 3.67 11.61 3.89 0.014 13.05 3.83 14.28 4.01 0.001 2.34 1.80 2.66 1.82 0.066 Plaque area (mm2) 8.63 3.47 9.47 3.71 0.016 7.51 2.82 7.88 2.94 0.181 1.12 1.75 1.60 1.76 0.005 Plaque burden (%) 79.0 8.3 80.2 8.5 0.143 56.4 8.1 54.3 7.8 0.007 22.6 8.2 25.9 7.3 <0.001 Minimal lumen diameter (mm) 1.47 0.23 1.48 0.25 0.660 2.41 0.37 2.66 0.45 <0.001
Maximal lumen diameter (mm)
1.75 0.37 1.77 0.38 0.591 2.86 0.40 3.00 0.41 <0.001
Lumen eccentricity 0.86 0.10 0.85 0.10 0.711 0.84 0.08 0.89 0.11 <0.001 Presence or absence of
calcium (%)
0.987
No 114 (36.4) 61 (36.5)
1 quadrant (1w90) 130 (41.5) 67 (40.1) 2 quadrants (91w180) 41 (13.1) 24 (14.4) 3 quadrants (181w270) 15 (4.8) 9 (5.4) 4 quadrants (270w360) 13 (4.2) 6 (3.6) Largest continuous arc of
calcium ()
45.5 58.8 51.8 67.0 0.306
Summed arc of calcium () 54.3 69.3 60.7 75.0 0.362
Remodeling pattern (%)* 0.802
Positive remodeling 94 (30) 46 (28)
Intermediate remodeling 83 (27) 43 (26) Negative remodeling 132 (42) 75 (45) IVUS-VH
Fibrous tissue (% of total plaque area)
27.70 16.07 26.70 14.69 0.504 27.30 10.99 21.71 8.86 <0.001 0.41 15.11 4.99 15.22 0.002 Fibrofatty tissue (% of total
plaque area)
52.70 22.81 54.00 21.61 0.551 31.49 19.77 30.08 17.65 0.440 21.25 20.07 23.92 17.17 0.139
Necrotic core (% of total plaque area)
15.64 10.23 15.48 9.94 0.867 28.58 10.70 30.65 10.12 0.043 13.03 10.96 15.17 10.65 0.044 Dense calcium (% of total
plaque area)†
3.95 6.02 3.82 5.81 0.822 12.56 11.21* 17.56 12.90* <0.001 8.56 10.13 13.74 12.47 <0.001
Values are mean SD or n (%). *7 are missing data. †The polymeric or metallic struts are detected as (pseudo)calcium on IVUS-VH.
IVUS-VH¼ intravascular ultrasound-virtual histology.
treated vessel, pre-procedural MLA, pre-procedural lumen eccentricity, plaque area, and vessel area (all measurements at the site of MLA). In addition, pres- ence or absence of calcium as well as arc of calcium at the site of MLA, tissue composition at the site of MLA, remodeling index (11), type of stent/scaffold, and maximal expected inner device or balloon diameter throughout procedure (in cases with or without post- dilation) were also included in the logistic regression analysis. In the multivariate model, MLA was not included due to strong interaction with plaque area and vessel area. Statistical analyses were performed with SPSS version 23.0.0 software (IBM, Armonk, New York).
RESULTS
BASELINE CHARACTERISTICS. Of 501 patients with 546 lesions who were enrolled in the ABSORB II trial, 445 patients with 480 lesions (291 patients with 313 lesions in the Absorb arm and 154 patients with 167 lesions in the Xience arm) had both pre- procedural and post-procedural IVUS analyses for acute lumen area gain assessment (Figure 1). There were no significant differences in baseline patient demographics and pre-procedural angiography data (Table 1).
DIFFERENCES IN PROCEDURAL IMPLANTATION STRATEGY BETWEEN ABSORB AND XIENCE.
Table 1indicates the differences in procedural strat- egy between Absorb and Xience. Pre-dilation strategy was comparable between both arms. At the time of the device implantation, no differences in device size selection and expected inner device diameter were observed, whereas maximal pressure during device implantation was higher in Xience than in Absorb. At the time of post-dilation, nominal diameter of the balloon, maximal pressure, and expected balloon diameter were smaller in the Absorb arm than in the Xience arm.
IVUS ANALYSIS. A representative case of acute gain in MLA is presented in Figure 2. Overall, the pre- procedural MLA was comparable between the 2 arms. However, pre-procedural vessel area (Xience 11.61 mm2 vs. Absorb 10.71 mm2, respectively; p ¼ 0.014) and plaque area (Xience 9.47 mm2vs. Absorb 8.63 mm2, respectively; p¼ 0.016) at the site of MLA were significantly larger in the Xience arm than in the Absorb arm. The post-procedural lumen area at the site of pre-procedural MLA was significantly smaller in the Absorb arm (5.55 mm2vs. 6.40 mm2, respec- tively; p < 0.001). The amount of change in plaque area and plaque burden was significantly smaller in
FIGURE 3 Cumulative Frequency Distribution Curve of Pre- and Post-MLA and Acute Gain
Cumulative frequency distribution curve of AG at the MLA site pre-procedure [AG¼ (MLApost– MLApre)] for Absorb and Xience. Pre-procedural MLA was similar between the 2 arms. The post-procedural lumen area at the site of the pre-procedural MLA was signifi- cantly smaller in the Absorb arm than in the Xience arm (5.55 mm2vs. 6.40 mm2, respectively; p< 0.001). The amount of change in lumen area was significantly smaller in the Absorb arm than in the Xience arm (3.46 mm2vs. 4.27 mm2, respectively; p< 0.001).
AG¼ acute gain; MLA ¼ minimal lumen area.
FIGURE 4 Device Expansion of Absorb and Xience
When device expansion was defined as the ratio of post-procedural lumen area at the site of the pre-procedural MLA to the expected inner device area calculated from the largest balloon used during procedure, the Absorb scaffold achieved, on average, 62 12% only of the predicted lumen area, whereas the Xience stent achieved 71 15% (p < 0.001).
MLA¼ minimal lumen area.
the Absorb arm than in the Xience arm (1.12 mm2 vs.1.60 mm2, respectively; p ¼ 0.005; and 22.6%
vs.25.9%, respectively; p < 0.001). The increase of vessel area tended to be smaller in the Absorb arm (2.34 mm2vs. 2.66 mm2, respectively; p¼ 0.066). As a result, there were significant differences in acute gain for the minimal lumen areas (3.46 mm2 vs.
4.27 mm2, respectively; p< 0.001) (Table 2,Figure 3).
DEVICE EXPANSION IN MINIMAL LUMEN AREA.
When device expansion (16,17) was defined as the ratio of post-procedural lumen area at the site of pre- procedural MLA to the expected inner device area calculated from the largest balloon used during pro- cedure, the Absorb scaffold achieved on average 62 12% of the predicted lumen area, whereas the Xience stent achieved 71 15% (p < 0.001) (Figure 4). Loca- tion of calcium as well as the arc of calcium and the amount of NC did not affect device expansion (Figure 5).
QCA MLD CHANGES AT DIFFERENT PHASES DURING PROCEDURE. Figure 6 shows the MLD by QCA and MLA by IVUS changes at different phases during the procedure in the patients who had both pre- and post- procedural IVUS analyses.
The Main difference in acute gain in MLD by QCA was observed at the time of device implantation (Xience vs. Absorb, Dþ1.50 mm vs. Dþ1.23 mm, respectively), whereas the gain from post-dilation was similar between the 2 arms (Dþ0.16 mm vs.
Dþ0.16 mm) when patients underwent post-dilation.
Acute recoil during device implantation was similar in both devices (Xience vs. Absorb, 0.20 0.18 mm vs. 0.19 0.19 mm, respectively; p ¼ 0.716), whereas acute recoil during post-dilation was larger in the Xience than in the Absorb (0.21 0.21 mm vs. 0.13 0.20 mm, respectively; p¼ 0.006).
PREDICTORS OF LOWER ACUTE GAIN. Lower acute gain (lowest tertile) occurred more frequently in
FIGURE 5 Relationship Between Circumferential Distribution of Calcium and Acute Gain
The relationship between circumferential distribution of calcium and acute gain (blue circles¼ Absorb; red circles ¼ Xience). Presence or absence of calcium as well as the arc of calcium by IVUS grayscale did not affect acute gain and device expansion at the site of minimal lumen area. IVUS¼ intravascular ultrasound; MLA ¼ minimal lumen area.
the Absorb arm than in the Xience arm (risk ratio:
3.04; 95% confidence interval [CI]: 1.94 to 4.76) (Table 3). Results of logistic regression analysis are summarized in Online Table 1. Sex, age, obesity, treated vessel, pre-procedural lumen eccentricity at the site of MLA, presence or absence of calcium as well as arc of calcium at the site of MLA, tissue composition at the site of MLA were not independent predictors for lower acute gain. The following vari- ables were significantly associated with lower acute gain in the multivariate model: Absorb use, maximal inner device or balloon diameter throughout proce- dure, vessel and plaque areas at the MLA site, and negative remodeling. Differences in IVUS acute gain between Absorb and Xience were consistent across these variables (Table 3).
DISCUSSION
MAIN FINDINGS.The mainfindings of this study are:
lower acute gain occurred more frequently in the Absorb arm than in the Xience arm (3.46 mm2vs. 4.27 mm2, respectively; p < 0.001; risk ratio: 3.04; 95%
CI: 1.94 to 4.76); plaque morphology at the MLA cross-section was not independently associated with acute gain; and on angiography, acute device recoil was comparable, but expansion of the device was different. The influence of post-dilation on MLD was somewhat limited.
IMPACT OF LESION MORPHOLOGY ON LUMEN ENLARGEMENT.There are conflicting data about the impact of lesion morphology on lumen enlargement. In
FIGURE 6 Minimal Lumen Diameter Changes by QCA and MLA Changes by IVUS at Different Phases of the Procedure
The minimal lumen diameter changes by QCA (line graph) and MLA changes by IVUS (bar graph) at different phases of the procedure in patients who had both pre- and post-procedural IVUS analyses. Change of MLD by QCA and MLA by IVUS of the Absorb and the Xience are depicted by blue and red, respectively. Dotted lines show minimal lumen diameter changes for those lesions that were not post-dilated, whereas solid lines show minimal lumen diameter change of the lesions that underwent post-dilation. Differences in acute gains were mainly observed at the time of device implantation (Dþ1.50 mm vs.Dþ1.23 mm), whereas the gain from post-dilation was similar between the 2 arms (Dþ0.16 mm vs.Dþ0.16 mm), when patients underwent post-dilation. IVSU ¼ intravascular ultrasound; MLA ¼ minimal lumen area; QCA ¼ quantitative coronary angiography.
previous reports, the expansion of drug-eluting stents was drastically influenced by IVUS (grayscale/virtual histology) plaque morphology (including the arc and length of lesion calcium) or quantitative lesion site geometry (lesion vessel area, plaque area, and plaque burden)(16–18). In the present study, the impact of plaque component on acute gain in lumen area was not retained in the multivariate analysis, although in uni- variate analysis, higher amounts of fibrotic plaque, necrotic core, and dense calcium showed lower acute gain in lumen area in both arms. In the present study, presence or absence of calcium as well as the arc of calcium by IVUS grayscale did not affect the acute gain and device expansion at MLA (Figure 5).
DIFFERENCES IN PROCEDURAL STRATEGY BETWEEN ABSORB AND XIENCE.Differences in acute perfor- mance can be driven not only by differences in the mechanical properties of the Absorb scaffold and the Xience metallic stent but also by different initial implantation strategies (6,19,20). Within precise boundaries of expansion (e.g., 3.0 to 3.5 mm for a de- vice of 3.0 mm), the stress-strain relationship of the metallic and polymeric struts are comparable, and the mechanical strength of the Absorb scaffold is not different from that of the metallic stent(21). However, when the scaffold is over-expanded (>3.5 mm for a
3.0-mm device), the strut crowns begin approaching their geometrical limit. The radial support is maxi- mized, while their tensile strength limit is also reached (22). Therefore, pre-dilation, optimal expansion, and avoidance of over-expansion are encouraged during the procedure with the Absorb device.
Maximal expected balloon diameters in cases with or without post-dilation were similar between Absorb and Xience. However, the ratio of post-procedural lumen area at the site of pre-procedural MLA to the expected inner device area calculated from the largest balloon used during procedure was smaller in the Absorb than in the Xience (Figure 4). This result might imply the necessity of more aggressive strategy during implantation and post-dilation of Absorb compared to Xience due to the device mechanical properties (i.e., tensile strength and radial force).
When QCA was performed to assess MLD changes at different phases during the procedure, differences between the 2 arms were already significant at the time of device balloon expansion (Dþ1.50 mm for Xience vs.
Dþ1.23 mm for Absorb; p < 0.01) (Figure 6), despite the fact that the expected inner devices’ diameters at implantation were similar in both arms. Acute device recoil amounts were comparable between the 2 arms (4). Despite less aggressive post-dilation in the Absorb
TABLE 3 Incidence of Lower Acute Gain
Absorb Xience Risk Ratio p Value for Interaction
All patients 41% (128/313) 19% (31/167) 3.04 (1.94-4.76)
Maximal expected diameter of balloon with or without post-dilatation
Lower tertile (#3.28) 70% (78/112) 35% (25/72) 4.31 (2.30-8.10)
Mid-tertile (>3.28, #3.40) 32% (37/117) 9% (3/34) 4.78 (1.37-16.64) 0.872
Higher tertile (>3.40) 16% (13/84) 5% (3/61) 3.54 (0.96-13.02) Vessel area at MLA site
Lower tertile (#9.10) 67% (75/112) 45% (21/47) 2.51 (1.25-5.04)
Mid-tertile (>9.10, <12.30) 33% (35/105) 13% (7/53) 3.29 (1.35-8.02) 0.305
Higher tertile ($12.30) 19% (18/96) 5% (3/67) 4.92 (1.39-17.46) Plaque area at MLA site
Lower tertile (#7.10) 69% (79/114) 46% (20/44) 2.71 (1.33-5.53)
Mid-tertile (>7.10, <9.95) 35% (35/101) 16% (9/58) 2.89 (1.27-6.56) 0.475
Higher tertile ($9.95) 14% (14/98) 3% (2/65) 5.25 (1.15-23.94) Remodeling*
Negative (RI<0.88) 41% (54/132) 17% (13/75) 3.30 (1.65-6.59)
Intermediate (0.88# RI#1.00) 39% (32/83) 26% (11/43) 1.83 (0.81-4.13) 0.835
Positive (RI>1.0) 43% (40/94) 15% (7/46) 4.13 (1.67-10.18)
*Remodeling index: 7 missing data.
MLA¼ minimal lumen area; RI ¼ remodeling index.
arm than in the Xience arm, the angiographic gains from post-dilation between the 2 arms were similar (Dþ0.16 mm vs.Dþ0.16 mm, respectively; p ¼ 0.97) (Figure 6). These angiographic analyses implied dif- ferences of the mechanical properties of both devices and the necessity of different procedural strategies for implantation.
The issue of recoil in QCA and IVUS seemingly somewhat contradicted each other. Another possi- bility is that the limited accuracy of the measure- ments by QCA and IVUS due to their resolutions could cause this contradiction. Their accuracy could be affected differently in implanted polymeric scaffolds and metallic stents. Moreover, the recoils were assessed by QCA and IVUS in a different fashion and settings. With IVUS, post-procedural MLA was compared to the virtual expected balloon dimensions at the time of maximal balloon inflation. In QCA, recoil was assessed from the difference in diameter between inflation balloon device and stented/
scaffolded diameter of the vessel post-implantation.
CLINICAL IMPLICATION.On the basis of previous reports(23) of disrupted polymeric scaffolds due to over-expansion, the protocol did not recommend post- dilation of the bioresorbable scaffold device. However, on angiography, a significant difference in the initial expansion was noted (Absorb< Xience). To achieve with the Absorb an acute lumen gain equivalent to that of the Xience, device balloon expansion with higher pressures and/or more aggressive post-dilation should be considered within the limits of the recommended diameters due to the difference in inherent device mechanical properties (i.e., tensile strength and radial force). Because the device balloon of the Absorb is semi-compliant, implantation with a high pressure might result in over-expansion of the device or edge dissection. One of the possible contributing factors to lower acute gain in the Absorb is the lack of sys- tematic post-dilation with a noncompliant balloon with a diameter of 0.25 or 0.5 mm larger than the nominal diameter of the polymeric device.
The following 3 clinical questions remain: How does an aggressive lesion preparation (pre-dilation, rota- tional atherectomy or cutting/scoring balloon) impact acute gain? Can a high implantation pressure with the Absorb device improve acute gain? How does an aggressive post-dilation impact acute gain? These questions should be answered in future trials.
STUDY LIMITATIONS. If the IVUS catheter could not cross the lesion, pre-dilation with a small balloon was performed. The incidence of pre-dilation before IVUS was similar between the Absorb and Xience arms, but initial lesion geometry and morphology could
not be evaluated in 12% of lesions. The analysts in core laboratory were not blinded to the device type, which could result in potential bias in data acquisition. Aorto- ostial lesions, bifurcations, chronic total occlusions, and lesions with heavy calcification on angiography were excluded from the present study. Thus, our conclusions should not be extrapolated to more com- plex lesion subsets. Lastly, in the present study, we did not evaluate—due to the small number of the events—
the relationship between IVUSfindings and clinical events such as scaffold thrombosis that is our current concern after implantation of Absorb.
CONCLUSIONS
At the site of pre-procedural MLA, the Absorb scaffold showed lower acute gain than Xience stents. To achieve acute gain equivalent to that of Xience, Absorb deployment may require preparation of the lesion and more aggressive strategies at implantation and post-dilation than the technique used in the ABSORB II trial due to the difference in inherent device mechanical properties.
ACKNOWLEDGEMENTS The authors thank Richard Rapoza, PhD, Luc Wasungu, PhD, and Susan Veldhof, RN, Abbott Vascular, for invaluable technical expertise.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Patrick W. Serruys, MD, PhD, International Centre for Circulatory Health, NHLI, Imperial College London, London SW7 2AZ, United Kingdom. E-mail:patrick.w.
PERSPECTIVES
WHAT IS KNOWN?It is warranted that the acute performance of Absorb matches that of metallic stents; however, concern exists about acute expan- sion and lumen gain with the use of Absorb.
WHAT IS NEW?Lower IVUS acute gain occurred more frequently in the Absorb arm than in the Xience arm. The plaque morphology at the MLA cross-section was not independently associated with acute gain. On angiography, device acute recoil was comparable but expansion of the device was different.
WHAT IS NEXT?Further studies are needed to eval- uate the impact of more aggressive strategies at implan- tation, pre- and post-dilation than the technique used in the ABSORB II trial on acute performance of Absorb.
R E F E R E N C E S
1.Serruys PW, Onuma Y, Garcia-Garcia HM, et al.
Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months.
EuroIntervention 2014;9:1271–84.
2.Onuma Y, Serruys PW. Bioresorbable scaffold:
the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation 2011;
123:779–97.
3.Diletti R, Serruys PW, Farooq V, et al. ABSORB II randomized controlled trial: a clinical evaluation to compare the safety, efficacy, and performance of the Absorb everolimus-eluting bioresorbable vascular scaffold system against the Xience everolimus- eluting coronary stent system in the treatment of subjects with ischemic heart disease caused by de novo native coronary artery lesions: rationale and study design. Am Heart J 2012;164:654–63.
4.Serruys PW, Chevalier B, Dudek D, et al. A bio- resorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial. Lancet 2015;385:43–54.
5.Brugaletta S, Gomez-Lara J, Diletti R, et al.
Comparison of in vivo eccentricity and symmetry indices between metallic stents and bioresorbable vascular scaffolds: insights from the ABSORB and SPIRIT trials. Catheter Cardiovasc Interv 2012;79:
219–28.
6.Zhang YJ, Bourantas CV, Muramatsu T, et al.
Comparison of acute gain and late lumen loss after PCI with bioresorbable vascular scaffolds versus everolimus-eluting stents: an exploratory obser- vational study prior to a randomised trial. Euro- Intervention 2014;10:672–80.
7.Kimura T, Kozuma K, Tanabe K, et al. A ran- domized trial evaluating everolimus-eluting Absorb bioresorbable scaffolds vs. everolimus- eluting metallic stents in patients with coronary artery disease: ABSORB Japan. Eur Heart J 2015;
36:3332–42.
8.Gao R, Yang Y, Han Y, et al. Bioresorbable vascular scaffolds versus metallic stents in patients with coronary artery disease: ABSORB China trial. J Am Coll Cardiol 2015;66:2298–309.
9.Ellis SG, Kereiakes DJ, Metzger DC, et al.
Everolimus-eluting bioresorbable scaffolds for coronary artery Disease. N Engl J Med 2015;373:
1905–15.
10.Ishibashi Y, Nakatani S, Sotomi Y, et al. Rela- tion between bioresorbable scaffold sizing using QCA-Dmax and clinical outcomes at 1 Year in 1,232 patients from 3 study cohorts (ABSORB Cohort B, ABSORB EXTEND, and ABSORB II). J Am Coll Cardiol Intv 2015;8:1715–26.
11.Inaba S, Mintz GS, Farhat NZ, et al. Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT. J Am Coll Cardiol Img 2014;7:70–8.
12.Mintz GS, Nissen SE, Anderson WD, et al.
American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ul- trasound studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:
1478–92.
13.de Jaegere P, Mudra H, Figulla H, et al. Intra- vascular ultrasound-guided optimized stent deployment. Immediate and 6 months clinical and angiographic results from the Multicenter Ultra- sound Stenting in Coronaries Study (MUSIC Study).
Eur Heart J 1998;19:1214–23.
14.Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A sta- tistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation 1995;91:1959–65.
15.Garcia-Garcia HM, Costa MA, Serruys PW. Im- aging of coronary atherosclerosis: intravascular ultrasound. Eur Heart J 2010;31:2456–69. 16.de Ribamar Costa J Jr., Mintz GS, Carlier SG, et al.
Intravascular ultrasound assessment of drug-eluting stent expansion. Am Heart J 2007;153:297–303.
17.He Y, Maehara A, Mintz GS, et al. Intravascular ultrasound assessment of cobalt chromium versus stainless steel drug-eluting stent expansion. Am J Cardiol 2010;105:1272–5.
18.Lee WS, Kim SW, Lee KJ, Kim TH, Kim CJ, Ryu WS. Under-expansions of drug eluting stents in patients with acute coronary syndrome are associated with plaque components as well as
vessel size or plaque burden. Circulation 2009;
120:S913.
19.Onuma Y, Serruys PW, Gomez J, et al., ABSORB Cohort A and B investigators. Comparison of in vivo acute stent recoil between the bio- resorbable everolimus-eluting coronary scaffolds (revision 1.0 and 1.1) and the metallic everolimus- eluting stent. Catheter Cardiovasc Interv 2011;78:
3–12.
20.Tanimoto S, Bruining N, van Domburg RT, et al. Late stent recoil of the bioabsorbable everolimus-eluting coronary stent and its rela- tionship with plaque morphology. J Am Coll Car- diol 2008;52:1616–20.
21.Ormiston JA, Serruys PW, Regar E, et al.
A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. Lancet 2008;371:899–907. 22.Onuma Y, Serruys PW, Perkins LE, et al.
Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bio- resorbable vascular scaffolds in a porcine coro- nary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial. Circulation 2010;122:
2288–300.
23.Onuma Y, Serruys PW, Muramatsu T, et al.
Incidence and imaging outcomes of acute scaffold disruption and late structural discontinuity after implantation of the Absorb everolimus-eluting fully bioresorbable vascular scaffold: optical coherence tomography assessment in the ABSORB cohort B trial (A Clinical Evaluation of the Bio- absorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). J Am Coll Cardiol Img 2014;7:1400–11.
KEY WORDS bioresorbable vascular scaffold, drug-eluting stent(s), intravascular ultrasound
APPENDIX For a supplemental table, please see the online version of this article.
